Sex Hormone-regulated CMG2 Is Involved in Breast and Prostate Cancer Progression.

BACKGROUND/AIM: Capillary morphogenesis gene 2 (CMG2) is involved in prostate and breast cancer progression. This study aimed to investigate sex hormone receptor-mediated regulation of CMG2 in breast and prostate cancer, and its implication in disease progression. MATERIALS AND METHODS: Expression of CMG2, oestrogen receptor (ER) and androgen receptor (AR) was determined in breast and prostate cancer cell lines, respectively, using real-time quantitative PCR (QPCR) and western blot. Association between CMG2 and sex hormone receptors was analysed in a number of transcriptome datasets. Immunochemical staining was performed in tissue microarrays of breast cancer (BR1505D) and prostate cancer (PR8011A). CMG2 expression was determined in 17ß-oestradiol treated breast cancer cells and AR over-expressing prostate cancer cells. RESULTS: CMG2 was found to be inversely correlated with sex hormone receptors in breast and prostate cancer. Lower expression of CMG2 was associated with a poor prognosis in ER (+) breast cancer but not ER (-) tumours. Both ER (+) breast cancer cell lines and AR (+) prostate cancer cell lines presented lower expression of CMG2, which was increased following sex hormone deprivation. Exposure to 17-ß-oestradiol and AR over-expression repressed CMG2 expression in breast cancer and prostate cancer cell lines, respectively. CONCLUSION: CMG2 is inversely correlated with ER and AR status in breast and prostate cancer, respectively. ER and AR mediate repression of CMG2 expression in corresponding cancerous cells.

NUPR1 and its potential role in cancer and pathological conditions (Review).

Nuclear protein­1 (NUPR1) is also known as Com­1 or p8. It is a protein primarily found in the nucleus of various cells, including cancer cells, and it has been found to play an important role in cell stress and stress­related apoptosis. Over the past two decades, NUPR1 has been firmly indicated to play a role in the development and progression of numerous types of cancer, as well as in a number of other pathological conditions, including pancreatitis, diabetes, neurological and inflammatory conditions. The past decade has witnessed a rapid understanding of the biological and cellular mechanisms through which NUPR1 operates on cells and the identification of new variant of the protein. Most importantly, there have been comprehensive studies on the clinical and pathological aspects of NUPR1 and its variant in multiple malignancies and identification of therapeutic methods by targeting the protein. The present review aimed to summarise the current knowledge relating to NUPR1 in human malignancies and to discuss the associated controversies and potential future prospects of this molecule.

The IL-17B-IL-17 receptor B pathway promotes resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway.

Interleukin 17B (IL-17B) is a pro-inflammatory cytokine that belongs to the IL-17 cytokines family and binds to IL-17 receptor B (IL-17RB). Here we found that high expression of IL-17B and IL-17RB is associated with poor prognosis in patients with breast cancer and that IL-17B expression upregulation is specifically associated with poorer survival in patients with basal-like breast cancer. We thus focused on IL-17B role in breast cancer by using luminal and triple negative (TN)/basal-like tumor cell lines. We found that IL-17B induces resistance to conventional chemotherapeutic agents. In vivo, IL-17B induced resistance to paclitaxel and treatment with an anti-IL-17RB neutralizing antibody completely restored breast tumor chemosensitivity, leading to tumor shrinkage. We next focused on the signaling pathways activated in human breast cancer cell lines upon incubation with IL-17B. We observed that IL-17B induces ERK1/2 pathway activation, leading to upregulation of anti-apoptotic proteins of the BCL-2 family. IL-17B-induced chemoresistance was completely abolished by incubation with PD98059, an inhibitor of the MAPK/ERK pathway, indicating that the ERK pathway plays a crucial role. Altogether our results emphasize the role of the IL-17B/IL-17RB signaling pathway in breast tumors and identify IL-17B and its receptor as attractive therapeutic targets for potentiating breast cancer chemotherapy.

Systematic Review and Meta-Regression of Factors Affecting Midline Incisional Hernia Rates: Analysis of 14,618 Patients.

BACKGROUND: The incidence of incisional hernias (IHs) following midline abdominal incisions is difficult to estimate. Furthermore recent analyses have reported inconsistent findings on the superiority of absorbable versus non-absorbable sutures. OBJECTIVE: To estimate the mean IH rate following midline laparotomy from the published literature, to identify variables that predict IH rates and to analyse whether the type of suture (absorbable versus non-absorbable) affects IH rates. METHODS: We undertook a systematic review according to PRISMA guidelines. We sought randomised trials and observational studies including patients undergoing midline incisions with standard suture closure. Papers describing two or more arms suitable for inclusion had data abstracted independently for each arm. RESULTS: Fifty-six papers, describing 83 separate groups comprising 14,618 patients, met the inclusion criteria. The prevalence of IHs after midline incision was 12.8% (range: 0 to 35.6%) at a weighted mean of 23.7 months. The estimated risk of undergoing IH repair after midline laparotomy was 5.2%. Two meta-regression analyses (A and B) each identified seven characteristics associated with increased IH rate: one patient variable (higher age), two surgical variables (surgery for AAA and either surgery for obesity surgery (model A) or using an upper midline incision (model B)), two inclusion criteria (including patients with previous laparotomies and those with previous IHs), and two circumstantial variables (later year of publication and specifying an exact significance level). There was no significant difference in IH rate between absorbable and non-absorbable sutures either alone or in conjunction with either regression analysis. CONCLUSIONS: The IH rate estimated by pooling the published literature is 12.8% after about two years. Seven factors account for the large variation in IH rates across groups. However there is no evidence that suture type has an intrinsic effect on IH rates.

Potential implication of IL-24 in lymphangiogenesis of human breast cancer.

Lymphangiogenesis is involved in the dissemination of malignant cells from solid tumours to regional lymph nodes and possibly to various distant sites. Lymphangiogenesis is regulated by vascular endothelial growth factor (VEGF)-C and VEGF-D. Interleukin (IL)-24 is known as a cytokine with potent antitumour and tumour-suppressive activity which functions through its receptor (IL-22R). Expression of IL-24 has been shown to be reduced in breast cancer, and the reduced expression is associated with lymphatic metastases and a poor prognosis. However, the involvement of IL-24 in lymphangiogenesis during lymphatic metastasis remains unclear. The aim of the present study was to determine whether there is an association between IL-24, IL-22R and lymphangiogenic factors and markers in breast cancer. Analysis of IL-24, IL-22R and lymphangiogenic factors in malignant breast tissue samples (n=127) revealed a correlation between increased expression of lymphangiogenic markers (podoplanin, Prox-1 and LYVE-1) and reduced levels of IL-24 and IL-22R. Samples stained with a high degree of positivity for lymphangiogenic factors and markers whereas staining for IL-24 was weak. In vitro assays showed that the average perimeter length of microtubules formed by endothelial cells treated with IL-24 was significantly reduced compared to the control. The growth of endothelial cells was significantly reduced when exposed to a high concentration of IL-24 (250 ng/ml). Treatment of HECV cells with IL-24 resulted in significantly reduced expression of VEGF-C (P<0.05) and VEGF-D (P<0.001). In conclusion, reduced expression of IL-24 and IL-22R in breast cancer is correlated with increased expression of specific lymphangiogenic markers. IL-24 suppressed in vitro growth and microtubule formation of endothelial cells. IL-24 may downregulate the expression of lymphangiogenic markers and factors although further research is required. This suggests that IL-24 plays a profound role in suppressing tumour lymphangiogenesis, thereby, reducing the likelihood of cancer metastasis via the lymphatic route.

A role for WISP2 in colorectal cancer cell invasion and motility.

BACKGROUND: WNT inducible secreted protein 2 (WISP2) has been linked with a variety of human cancer types and may contribute to cancer metastasis. The current study investigated the importance of WISP2 in colorectal cancer cells, examining the impact of targeting WISP2 on Caco-2 cell invasion and motility together with potential mechanisms of action. MATERIALS AND METHODS: WISP2 expression was targeted in Caco-2 cells using a ribozyme transgene system and successful knockdown was verified using reverse transcription-polymerase chain reaction (RT-PCR). The impact of WISP2 knockout (Caco-2(WISP2 KO)) on cell growth, adhesion, motility and invasion was examined using a number of in vitro functional assays. In vitro invasion assays were repeated in the presence of wingless-type MMTV integration site family (WNT) inhibitors (FH535 and IWP-2) to investigate the role of the WNT-signalling pathway in the regulation of cell invasion by WISP2. Quantitative-PCR was conducted to measure matrix metalloproteinase (MMP) expression in control [wild-type (Caco-2(WT)) and cells containing the empty pEF6 plasmid (Caco-2(pEF6))] and Caco-2(WISP2 KO) cells. RESULTS: WISP2 knockout resulted in a significant increase in Caco-2 cell invasion and motility (p<0.05 in comparison to wild-type and plasmid control Caco-2 cells). WISP2 knockout had no significant effect on Caco-2 cell growth rate in 3- and 5-day incubation and no significant impact on Caco-2 cell-matrix adhesion rates (p>0.05). Expression analysis of a number of MMPs indicated an insignificant up-regulation of MMP2, MMP9 (p>0.05) but significant up-regulation of MMP7 (p=0.025) in Caco-2(WISP2 KO) cells compared to controls. Inhibition of WNT signalling using FH535 and IWP-2 brought about a significant or borderline significant decrease in Caco-2(WISP2 KO) cell invasion (FH535 p=0.065) and (IWP-2 p=0.002) and negated the pro-invasive effect of targeting WISP2 in Caco-2 cells. CONCLUSION: WISP2 knockout significantly increased Caco-2 cell invasion and motility. Up-regulation of MMP2, -7 and -9 may indicate that WISP2 regulates invasion and motility through MMPs. Regulation of invasion by WISP2 may involve the WNT signalling pathway.